Project Summary Although over 100 COVID-19 vaccines are currently in development worldwide in response to the global public health emergency, most or all may suffer from the liability of eliciting anti-viral-spike antibodies (Abs) that enhance (ADE) either viral infection or COVID-19 disease, upon exposure of vaccinees to circulating SARS- CoV-2 viruses. This phenomenon was observed previously in humans for respiratory syncytial viruses and in preclinical studies for the closely related SARS and MERS viruses. Notably, none of these viruses currently have a licensed effective and safe vaccine available despite 15 (SARS) to 60 (RSV) years of effort by the scientific community. These facts raise the alarming possibility that all current COVID-19 vaccines that are not rationally designed to avoid ADE may fail, perpetuating the current global health emergency and eroding confidence in vaccines and in the medical scientific community. Many COVID-19 patients experience near-fatal or fatal immunopathologic ?storms? in lung, heart and blood starting at 7-14 days after onset of symptoms, which is approximately when the antibody response to the virus is rising or peaking. This suggests that immunopathologic ADE of disease enhancement in humans in the current emergency cannot be ignored in vaccine design. A few of the current vaccine candidates take a small step towards avoidance of ADE by restricting vaccine immunogens to the SARS-CoV-2 receptor binding domain (RBD), which is theorized to avoid ADE by minimizing immune complex formation without sacrificing virus neutralization epitopes. Others seek to steer the immune system away from harmful, pro-inflammatory vaccine responses using viral vectors and adjuvants. We propose to develop a unique vaccine in the pandemic that goes all the way down this road to incorporate only a single, neutralization, B-cell epitope, thereby maximally avoiding both ADE of viral infection and ADE of disease, as well as testing the ALVAC-alum platform we have previously validated for HIV to steer immunity towards a less inflammatory, protective state. Leveraging Rhesus macaques that are already purchased (no cost to this project for purchase), we will produce and test the protection afforded by the single, neutralization, B-cell epitope (Aim 1) as well as the immune response to the ALVAC-alum platform (Aim 2). The results may set the stage for a rapidly manufactured vaccine to emergently fill the ADE gap in the current COVID-19 vaccine landscape.